Antigen presentation is the process by which innate immune cells like macrophages and dendritic cells (antigen presenting cells, APC) acquire antigens and present them to T cells to initiate the adaptive immune response. How APCs shape the immune response by both degrading antigens and preserving antigens for presentation to T cells has been a long-standing area of interest. Recently, the mechanism of antigen recognition by APCs has been shown to affect the preference of MHC I versus MHC II antigen presentation pathways. For instance, mannose receptor mediated endocytosis on dendritic cells has been shown to route antigens toward MHC I antigen presentation, whereas scavenger receptor-mediated endocytosis has been associated with MHC II presentation (Burgdorf et al (2007) Science 316(5824):612-616).
Moreover, the functional outcomes of antigen presentation have been shown to be context-dependent. For instance, targeting antigens to DEC-205 using monoclonal antibodies induced tolerance under non-inflammatory conditions, but instead mediated immunogenicity under activating conditions by CD40L (Bonifaz et al. (2004) J Exp Med 199(6):815-824). Harnessing APCs to enhance the anti-tumor T cell response offers an exciting strategy for cancer immunotherapy. The ability of the T cell immune response to be successfully mobilized against cancer has been demonstrated through preclinical and clinical studies of anti-CTLA4 antibody for T cell activation (Callahan et al. (2010) Semin Oncol 37(5):473-484).
CD47 is a broadly expressed transmembrane glycoprotein with a single Ig-like domain and five membrane spanning regions, which functions as a cellular ligand for SIRPα with binding mediated through the NH2-terminal V-like domain of SIRPα. SIRPα is expressed primarily on myeloid cells, including macrophages, granulocytes, myeloid dendritic cells (DCs), mast cells, and their precursors, including hematopoietic stem cells. Structural determinants on SIRPα that mediate CD47 binding are discussed by Lee et al. (2007) J. Immunol. 179:7741-7750; Hatherley et al. (2007) J.B.C. 282:14567-75; and the role of SIRPα cis dimerization in CD47 binding is discussed by Lee et al. (2010) J.B.C. 285:37953-63. In keeping with the role of CD47 to inhibit phagocytosis of normal cells, there is evidence that it is transiently upregulated on hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo.
Phagocytosis by macrophages relies on the cell's recognition of pro-phagocytic (“eat me”) and anti-phagocytic signals (“don't eat me”) on a target cell. Blocking anti-CD47 monoclonal antibody (mAb) induces macrophage phagocytosis of cancer cells by inhibiting an important anti-phagocytic (“don't eat me”) signal, allowing pro-phagocytic signals to dominate (Majeti et al. (2009) Cell 138(2):286-299; Willingham et al. (2012) P.N.A.S. 109(17):6662-6667.). CD47 is highly expressed on cancer cells and pathogen-infected cells compared to normal cells, and interacts with the ligand SIRPα on macrophages. This results in phosphorylation of ITIM motifs on SIRPα's cytoplasmic tail and the recruitment of SHP-1 and SHP-2 phosphatases, which is thought to block phagocytosis by preventing myosin-IIA accumulation at the phagocytic synapse.
Therapeutic efficacy of blocking anti-CD47 mAbs against xenograft human cancers growing in immunodeficient mice, including cancers such as leukemia, lymphoma, multiple myeloma, and solid tumors, including breast, colon, prostate, bladder cancers, and sarcomas has been demonstrated. Whether the adaptive immune response can also be recruited against the cancer following anti-CD47 mAb treatment has not been determined.